In this proposal, we will continue to exploit the mouse strains established in the first funding period to address the mechanisms of the Mre11 complex's actions in chromosome metabolism. In addition, we will test the hypothesis that proteins interacting with the Nbs1 N terminus are critical for regulation of DNA damage responses. We expect that these approaches will continue to provide important insights regarding the role of the Mre11 complex in the maintenance of genomic integrity and the suppression of malignancy. The governing hypothesis of this proposal is that, from its association with chromatin, the Mre11 complex functions as a hub of the DNA damage response. We propose that this association is a prerequisite for its influence on sister chromatid interaction during DSB repair and DNA damage signaling. In addition, we propose that its signaling function takes place via protein interactions that include those governed by the N terminus of Nbs1. We will test these hypotheses through a combination of biochemical and genetic approaches in human cells and mice.